(PhO)₃P·Cl₂-Promoted Bischler-Napieralski-Type Cyclization: a Mild Access to β-Carbolines

Abstract

A novel mild access to the β-carboline skeleton is described. The reaction is a Bischler-Napieralski-type cyclocondensation, promoted by (PhO)₃P·Cl₂, which is performed in dichloromethane at -30 °C. The products are easily obtained in good yields and do not require further chromatographic purification.

triphenyl phosphite - chlorine - indoles - alkaloids - ­Bischler-Napieralski cyclizations

References

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17

Synthesis of Tryptamine Amides (1a-d); General Procedure.
Tryptamine (4500 mg, 28 mmol) was dissolved in dry CH₂Cl₂ (20 mL) in a two-necked 100 mL flask, and Et₃N (4.3 mL, 30.8 mmol) was added. The appropriate acyl chloride (1.1 equiv) dissolved in CH₂Cl₂ (10 mL) was then cautiously dropped in, under vigorous stirring. The reaction mixture was heated to reflux for 90 min, until TLC showed disappearance of starting tryptamine. Thereafter, the mixture was washed with 10% HCl, sat. NaCl and finally with H₂O, each time extracting with CH₂Cl₂. The organic phases were pooled, dried over MgSO₄ and evaporated in vacuo, to provide a thick foam which was triturated with light petroleum, thus affording the desired amide as a reddish-brown fine powder (70-92% yield).

18

The role of the base is to shield (PhO)₃P·Cl₂ from the action of adventitious HCl, which is reported to enhance its degradation into an inactive form. For more detailed mechanistic insights, see Ref. 1,2a.

19

Synthesis of Harmalane Hydrochloride ( 2a).
In a three-necked 50 mL round bottom flask, anhyd CH₂Cl₂ (15 mL) was cooled to -30 °C under argon atmosphere. Triphenyl phosphite (1.2 mL, 4.6 mmol) was added and Cl₂ was bubbled in, until the solution became bright yellow. The color was discharged by addition of a few drops of triphenyl phosphite, and tryptamine acetamide 1a (850 mg, 4.2 mmol) was then added, quickly followed by Et₃N (671 µL, 4.83 mmol). The reaction was stirred over a 2-hour period, then the cold bath was removed and the mixture left to stir at r.t. After 12 h, a conspicuous yellow solid had precipitated and was recovered by centrifugation, thus affording 909 mg (98%) of harmalane (2a) as hydrochloride. ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.79 (3 H, s, Me), 3.19 (2 H, t, J = 8.1 Hz, CH ₂CH₂N), 3.88 (2 H, t, J = 8.1 Hz, CH₂CH ₂N), 7.78-8.14 (4 H, m, arom.), 12.87 (1 H, br, NH), 13.07 (1 H, br, HCl). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 19.0, 19.1, 42.1 113.7, 121.6, 122.2, 123.0, 124.3, 126.8, 128.5, 140.9, 167.2. MS: m/z = 221 (M⁺), 207, 182, 154, 128, 91, 77, 63, 44. Anal. Calcd for C₁₂H₁₃ClN₂: C, 65.31; H, 5.94; N, 12.69. Found: C, 65.42; H, 6.05; N, 12.73.

20

Synthesis of 1-Phenyl-4,9-dihydro-3 H -β-carboline ( 2b).
By close analogy to the procedure described above, triphenyl phosphite (1.16 mL, 4.3 mmol) was dissolved in anhyd CH₂Cl₂ (14 mL) at -30 °C under argon atmosphere. Then, Cl₂ was bubbled in, until the solution turned intensely yellow. The color was discharged by addition of a few further drops of triphenyl phosphite and tryptamine benzamide 1b (1000 mg, 3.9 mmol) was added, quickly followed by Et₃N (637 µL, 4.58 mmol), and the system was maintained under vigorous stirring over 2 h at -30 °C before removing the cold bath. After an additional 12 h period at r.t., the dark mixture was treated with 10% HCl and extracted with CH₂Cl₂ (4 × 10 mL). The aqueous phase was then basified to pH 10 with 20% NaOH and repeatedly extracted with CH₂Cl₂ (4 × 15 mL). The organic phases were pooled, dried and rotary evaporated, to afford 2b (505 mg, 51%) as a yellow fine powder (mp 196-198 °C). ¹H NMR (200 MHz, CDCl₃): δ = 2.99 (2 H, t, J = 8.5 Hz, CH ₂CH₂N), 4.06 (2 H, t, J = 8.5 Hz, CH₂CH ₂N), 7.10-7.85 (9 H, m, arom.), 8.24 (1 H, br, NH). ¹³C NMR (50 MHz, CDCl₃): δ = 19.2, 48.8, 111.9, 117.9, 119.9, 120.4, 124.6, 127.8, 128.8, 129.9, 136.5, 137.6, 159.4. Anal. Calcd for C₁₇H₁₄N₂: C, 82.90; H, 5.73; N, 11.37. Found: C, 82.85; H, 5.64; N, 11.49.

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24

Application of Banwell’s method [14] to substrate 1b failed to give the expected β-carboline 2b.